P-3: Radiation Inducible TNF-a Therapy for Prostate Cancer

P-3：前列腺癌的放射诱导 TNF-a 疗法

• 批准号: 8055506
• 负责人: RALPH R WEICHSELBAUM
• 金额: $ 30.02万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-31 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055506
• 关键词: Ablation; Adenovirus Vector; Androgens; Biological Markers; Blood Vessels; Cancer Model; Cancer Patient; Cell Death; Clinical; Clinical Trials; Complementary DNA; DNA Sequence; Data; Development; Dose; Endothelial Cells; External Beam Radiation Therapy; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Gleason Grade for Prostate Cancer; Goals; Head and neck structure; Human; Intensity-Modulated Radiotherapy; Local Therapy; Locally Advanced Malignant Neoplasm; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Methods; Molecular Profiling; NF-kappa B; Operative Surgical Procedures; Outcome; Patient Selection; Patients; Pelvis; Pharmaceutical Preparations; Phase; Phase I/II Trial; Phase II/III Trial; Population; Production; Prognostic Factor; Prostate; Prostate Cancer therapy; Prostatectomy; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radio; Rectal Cancer; Recurrence; Research Personnel; Resistance; STAT1 gene; Safety; Staging; Staining method; Stains; TNF gene; Testing; Therapeutic; Thrombosis; Toxic effect; Tumor Necrosis Factor-alpha; Up-Regulation; Xenograft Model; antitumor agent; cohort; design; disorder control; high risk; human TNF protein; improved; inhibitor/antagonist; irradiation; outcome forecast; overexpression; p65; pre-clinical; programs; radiation resistance; rectal; standard care; success; tumor; vector

Outcomes for patients with high risk localized prostate cancer treated with standard radiotherapy and androgen ablation are unacceptable. The addition of radiation sensitizing agents to radiotherapy is useful in other locally advanced cancers such lung and rectal cancer. TNF-alpha is a potent radiosensitizing antitumor agent, but toxicity limits its use as a systemic drug. Ad.Egr-TNF.11D (TNFeradeTM, GenVec, Gaithersburg, MD) is a replication deficient E1, E3, E4 deleted adenoviral vector that encodes radio- inducible DNA sequences upstream from a cDNA for human TNF-alpha. Ad.Egr-TNF.11D is activated following radiation to produce intratumoral therapeutic levels of TNF-alpha and enhanced tumor regression via vascular destruction and thrombosis. To develop this concept clinically an early phase clinical trial of Ad.Egr-TNF.11D, radiotherapy, and androgen ablation to determine if the combination is safe in these patients will be conducted. It is recognized that addition of inducible local TNF is unlikely to be sufficient for this population and that additional measures need to be explored. Furthermore, markers for predicting whih patients are most likely to benefit need to be developed. In regards to the former, activation of NFkB by both TNF and radiation may be critical to promoting survival and inhibiting both the cancer and endothelial cell death required for successful treatment. Therefore, it will be determined if inhibition of NFkB activation through use of the triterpenoid CDDO or an adenoviral vector that inhibits NFkB by encoding a non-degradable ("super- repressor") form of IKBa (Ad.CMV.IkBa) further enhances the activity of Ad.Egr-TNF.11D and radiotherapy in preclinical prostate cancer models. Finally, it has been demonstrated that STAT1 is induced by radiation and preliminary evidence suggests that upregulation of STAT1 predicts for resistance to irradiation, raising the hypothesis that patients with baseline elevated tumor STAT1 levels will respond less well to standard radiation. It will thus be determined if STAT1 and NFkB overexpression are associated with recurrence in a historical group of locally advanced prostate cancer patients with the prediction that the association will be stronger in patients treated with radiotherapy than in patients treated with surgery.

高危局限性前列腺癌患者接受标准放疗和联合治疗的结果 雄激素消融是不可接受的。在放射治疗中添加辐射增敏剂在 其他局部晚期癌症，如肺癌和直肠癌。肿瘤坏死因子-α是一种有效的放射增敏物质 抗肿瘤药物，但毒性限制了其作为全身药物的使用。Ad.Egr-TNF.11D(TNFeradeTM，GenVec， Gaithersburg，MD)是一种复制缺陷的E1、E3、E4缺失的腺病毒载体，编码 人肿瘤坏死因子-α基因上游的可诱导DNA序列。Ad.Egr-TNF.11D被激活 放疗后肿瘤内产生肿瘤坏死因子-α的治疗水平和增强的肿瘤消退 通过血管破坏和血栓形成。为了在临床上发展这一概念，进行一项早期临床试验 Ad.Egr-TNF.11D、放射治疗和雄激素消融，以确定联合应用是否安全 将对患者进行检查。 人们认识到，增加可诱导的局部肿瘤坏死因子对这一人群不太可能是足够的，并且 还需要探索其他措施。此外，预测哪些患者最有可能的标志物 要想受益，就需要发展。对于前者，肿瘤坏死因子和辐射对NFkB的激活作用 可能是促进生存和抑制癌症和内皮细胞死亡所需的关键 治疗成功。因此，将确定是否通过使用 三萜类CDDO或腺病毒载体，通过编码不可降解的(“超- 抑制子“)形式的IKBA(Ad.CMV.IkBA)进一步增强Ad.Egr-TNF.11D的活性和放射治疗 在临床前前列腺癌模型中。 最后，已经证明STAT1是由辐射诱导的，初步证据表明 STAT1上调可预测对辐射的抵抗，从而提高了基线患者的假设 升高的肿瘤STAT1水平对标准辐射的反应较差。因此将确定STAT1是否 NFkB过度表达与局部进展性前列腺病复发相关 癌症患者预测，这种关联在接受放射治疗的患者中会更强 而不是接受手术治疗的患者。